Vial Presents: Challenges in Squamous Cell Carcinoma Trials featuring Dr. Andrew South


Dr. Andrew South, Professor in the Department of Dermatology & Cutaneous Biology at Thomas Jefferson University, and Simon Burns, CEO and Co-Founder of Vial, dive deep into the current challenges in SCC trials.

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Simon Burns: Dr. South, thank you so much for joining us and chatting with us about squamous cell carcinoma. We love to chat with you kind of have a lightning fire round questions about squamous cell carcinoma with biotech companies in mind. To kick us off, what are the common pitfalls that you see in squamous cell carcinoma, trial design? 

Dr. Andrew South: I think recruitment. I mean, it depends on what stage of SCC you’re looking at. So if you’re looking at late stage metastatic disease, then recruitment’s challenging. If you’re just looking at precursor lesions or early stages, then, that’s not a problem.

But that definitely can be an issue with trials in cutaneous SCC

Simon Burns: How do you advise early stage companies who are running trials on how to recruit for SCC well? 

Dr. Andrew South: Well, it’s all about centers that see a lot of patients, their volume throughout the year. Oftentimes, certainly if it’s late stage, oftentimes you’d probably want to get their otolaryngology departments on board as well.

Cause they’re the guys, the head and neck surgeons, that see the most aggressive late-stage squamous cell carcinoma of the skin, and they’re usually associated with SCC at the head. So that’s definitely something to bear in mind. 

Simon Burns: Great. What’s the most exciting development you’ve seen in SCC that you did not expect?

Dr. Andrew South: I’m speaking from personal experience, so we were running a trial of an experimental therapeutic in a rare disease group that predisposed a very aggressive squamous cell carcinoma and we’ve treated one patient, but we saw a complete response and that in the world of oncology is pretty rare and super exciting, so that’s kind of preoccupying my excitement at this point in time.

But of course, the responses we’ve seen with cemiplimab in cutaneous SCC, so PD-1 inhibitors, is also exciting as well. And I guess might’ve been predicted in terms of mutation burden, and it’s great to see a company get into that space, but obviously we’re early days, so we’ll have to see how long those responses last for. But it’s really encouraging and I guess that’s probably pretty exciting from the global SCC point of view. 

Simon Burns: Incredibly exciting. When’s the last time you changed your mind on something in SCC, a thesis you had of what would be effective that you ended up changing your mind on or vice versa?

Dr. Andrew South: It’s not necessarily treatment based, but it’s more genomic space because that’s one of my areas of expertise. I had the assumption that mutations were key in squamous cell carcinoma of the skin, and that they would stratify aggressive disease from early or benign disease.

And the studies thus far haven’t really borne that out. I think we see a high burden of mutation. We see an equal spread of particular mutations in a benign SCC compared to a late stage aggressive SCC. So I guess I’ve changed my mind on exactly how mutations key to driving progression of SCC and the work we’ve done has shifted our focus to the micro environment now.

And so that’s been a change of a view that’s not necessarily recent, that’s been developing over the last decade. Nevertheless, that’s not what we predicted to start with. 

Simon Burns: I’d love for you to take us up five years. What is the world of SCC talking about in five years time? 

Dr. Andrew South: I think it’s looking at combinations with immunotherapy if certain targeted therapies haven’t really come to the surface, floated out there and shown good efficacy and that they’re still in the development I believe.

But I think it’s the combination therapies with immunotherapies, with checkpoint inhibition and different types of checkpoint inhibition that are coming through. I think that in five years time will be the sort of discussion from a therapy point of view. And then I think what will emerge will be this sort of precision medicine, but really taking a deep dive into precision medicine in terms of, patient phenotyping, genomic profiles and how an individual responds to a given therapy.

Simon Burns: Would love your take on the current therapeutics going through clinical trials. How optimistic you are, give us a 1-10 scale on your level of optimism and what brings that number up and what brings that number down. 

Dr. Andrew South: So that’s kind of a tricky question. There’s a number of different therapies and some of them, there seems to be still a focus on EGFR inhibition for instance, that I personally don’t believe is necessarily the right way forward. I revert back to this experimental therapeutic that we’re working with that seems, you know, obviously has given us this complete response. So I’m optimistic. I would give an eight or a nine.

I think some of the things that could bring that down are fixation with older therapies that I think like EGFR that really have been thrashed out. And okay, you can combine those with other approaches, but, looking at the data and looking at the reasoning behind the whole mechanism of EGFR and [00:05:00] inhibition, I personally, I think is a mistake.

 And then what raises that number up to a 10 would be again, getting back to this sort of precision approach. And precision approach includes genomics, but also really good clinical phenotyping and patient phenotyping, and marrying those two factors across the board from patients behavior, patient’s recollection of disease, to histological characterization of their disease, their genomic characterization of the disease, and then their response or lack of response to a given therapy. And I think the better we get at doing that, we’re going to shift that number up towards the goals of really matching therapies to patients.

Simon Burns: Say the NIH or a life sciences venture fund, were to give you $250 million to allocate across some of these new approaches. Where would you spend that money? 

Dr. Andrew South: Yeah, that’s always a difficult question to answer and 250 million is a nice number. I would definitely appreciate that from any source. I think it really is all about that sort of deep clinical phenotyping, patient phenotyping, and then looking at the, you know, the wide range of approaches we have for analyzing and interrogating those tumors. I would certainly spend a good amount of that money on looking at complimentary analyses and figuring out how best we can get the information we need from a tumor biopsy or an excision and really thorough interrogate that in terms of its spacial profile, its protein profile, its RNA profile, his DNA profile, it’s clonal heterogeneity within the tumor. And then really drive that forward from a profiling point of view. And then also, that sort of money would be great to support a clinical trials unit within the institution that I work at and really make that a streamlined a process that takes little time, so we might invest that in some of the IRB, we might invest that in just the trial administration. Then we might even provide funds to give incentives to patients to get on board on the trial. I mean, that’s a decent amount of money, so that’s where my mind would go if that check ever came in the post, in the mail. 

Simon Burns: Or direct deposit, however it shows up. 

Dr. Andrew South: Yes, absolutely, one doesn’t care. 

Simon Burns: Let’s run through our segment of overrated, underrated lightning fire topics to get your read on. Is this space overrating or underrating the potential. First off, genomic profiling in squamous cell carcinoma.

Dr. Andrew South: Underrated, but the caveat there being it depends on what genomic profiling you’re looking at. I already mentioned about the somatic mutation profiling, but you should look at the context of, you know, what are you looking at? And what’s within that tumor sample biopsy excision, however you look at it.

Simon Burns: Let’s talk about a correlative studies, what is your overrated, underrated there? 

Dr. Andrew South: I think they’re underrated and companies should invest more in them. Obviously company’s focus is getting patients on trial, that’s key. But then understanding what’s going on in the trial, is really only achieved with good correlative studies.

Simon Burns: Let’s keep powering through here: tumor heterogeneity.

Dr. Andrew South: Heterogeneity is really underrated, I think, and arguably the cause of a lot of remission for certain therapies. And certainly in the early days of targeted therapy, we see recurrence or adaptation of the tumor and lots of mechanisms, whether that’s an existing heterogeneity or whether it’s adaptive over time.

But I think giving a heterogeneity score to a tumor and figuring out how that correlates with response is also going to be profitable. 

Simon Burns: Precision inclusion criteria

Dr. Andrew South: It’s kind of harking back to this whole genomics thing, but if you take a tumor biopsy for diagnosis, you want to know everything you can about that tumor. Obviously where you take that biopsy from is going to influence the output. But nevertheless, is that tumor really desmoplastic as that tumor got a lot of immune infiltration. You take the biopsy, you diagnose, you then treat the patient, and then you look at what’s hopefully complete response or partial response. And you look at what’s there and you then start correlating that with what you saw before. And that gives you a huge insight into mechanism and then patient response. And that will help you filter through to say, only 20% of the patients responded, but you will know why, or you will have some idea of why. 

Simon Burns: Phenomenal. This is great. Thank you for taking the time.

What did we not ask you that we should have asked you about the field and upcoming advances in squamous cell carcinoma

Dr. Andrew South: There’s a barriers. I think your study team has to be really on board. So radiologists, oncologists, obviously the dermatologist, and we’re talking about cutaneous SCC here.

I think that can sometimes be disconnected at a given institution that you’re working at. So I think study team is key there. 

In terms of questions that you didn’t ask me about, I think the study design.

 You’ve got to really know your disease really well. [00:10:00] You’ve got to think about what your endpoints are if you want to achieve them. I study a rare disease, the genetic disease where patients have tons of blistering, so the skin blisters, they have tons of wounds. Some of the early trials there really didn’t understand how wounds behave in a patient. And they failed because they were thinking, our intervention is going to heal these wounds, and we’re going to compare it to wounds that have the vehicle or the control, and some of those control vehicle wounds also healed when they were having patient visits.

And so that just completely confounded the analysis and it failed and they invested huge amounts of money. You’ve got to know the disease and you’ve got to be absolutely sure that your endpoints are achievable and the they’re not too ambitious, like complete wound healing for 200 days or something in that instance, again, it’s the sort of response that you might want to see in a precancerous cancerous late-stage disease. What’s the measure, what do you really want to see? 

And then lastly, knowing the mechanism of your intervention is absolutely key and, to give a good example, is this experimental therapeutic that I’m working for at the moment and in this rare disease where we’ve seen this complete response, and there’s been a lot of data in the literature saying that there is mechanism X mechanism Y, mechanism Z. And I think that the company invested a huge amount of money in a single indication. They went all the way to phase III and it unfortunately failed. And this is a personal opinion, of course, I think it’s because they took verbatim some of the early scientific papers and studies on the mechanism of action of this drug, married that with what’s known about that particular indication and then thought, great, this is it. We’ve got to go for it. And in reality, subsequent analyses have shown that there’s differences in mechanism of action of the drug. And had they spent a bit more time in the pre-clinical development, they might’ve not spent so much money on a failed phase III trial. 

Simon Burns: I was going to ask you what the rare diseases that you worked on with the wound healing endpoint and what is the challenge in endpoint design there? Do you have a better approach on how to track the progression.

Dr. Andrew South: Yeah. So the rare disease is epidermolysis bullosa, and it’s actually a group of diseases and they’re a genetic disease. So they’re caused by mutations in genes that hold the skin together to the structural protein genes code for structural proteins. Now there are over 20 genes that can be mutated that lead to skin fragility. And you don’t get combinations, rarely get combinations, but it’s two mutations generally in one gene given it’s generally a recessive disease, although they’d have some dominant forms as well.

And I think initially folks went in and said, we’re going to test this cream in wounds, and the creams had some benefit in some subtypes of this one to 20 different genes, but that data’s not going to help you in phase III because you design the trial to encompass all your recruited patients.

And of course it’s a rare disease, so the companies might’ve gone into that disease and thought, we’re only going to get enough patients that we include all the subtypes of epidermolysis bullosa. And in fact, the subtypes actually quite different in their clinical presentation, their behavior and their wound healing.

And so that I think an error. So understanding the disease there would have helped in those early clinical trials. Now companies are a bit more focused to say, we’re only going to look at this one subtype of disease. We’re only going to include patients that have got these sorts of wounds and we’re able to match them on reciprocal body sites or the same body site. And then also we’re not going to say the end point is a hundred percent healed wounds. We’re going to say an improvement over control and measure it that way. And so there’s those sorts of nuances that I guess, had some of the early companies engaged the correct KOLs with, then they might’ve avoided that.

Simon Burns: Last question and I’ll let you go. Same question that we asked for squamous cell carcinoma, but for EB. What are the most exciting developments in the early therapeutics, what are you tracking to see how it performs in the clinic? 

Dr. Andrew South: We’ve had positive top-line data from the phase III study from a company called Krystal Biotech who have a novel gene therapy vector, HSV-1 based, where they’re delivering the missing protein in a particular type of EB, the recessive dystrophic subtype and where they are able to deliver a large gene that has been challenging for other gene therapy vectors.

And so I believe, obviously that is a conversation they’ll have with the FDA, I believe they will get an approval late this year. And that’s fantastic news. It’s not a complete cure, but it certainly is something that the patients can use and will provide benefits, so that’s super exciting.

And then there’s actually a slew of different approaches. There’s recombinant protein infusions into the bloodstream which may or may not give us sort of more systemic, curative outcome. There are other approaches such as engineering or correcting skin cells from patients. So you take a [00:15:00] biopsy, you grow the skin cells out, and the skin is great because it renews every 30 days. And so it has a high proliferative capacity. So you can really expand those cells in the lab, put the gene back in and then graft those cells back onto a patient or inject those cells, in the case of dermal fibroblasts. Those are great approaches as well. The other potential approval that actually had approval in Europe by the EMA is a topical applications called Oleogel and includes active ingredients extracted from birch tree bark, they’re quite well characterized in terms of their wound healing properties.

The EMA have approved that for some subtypes of EB and the company Amryt Pharma are going back and forth with the FDA now in terms of what they would like to see for approval. So there are other approaches, the premature termination code on read through, which is drugs based on data from amino glycosides first seen in cystic fibrosis, where if a patient has a mutation that generates a what’s called a premature termination code on.

So mutates from, let’s say analogizing to a stop, you get a truncated protein, but it’s been seen that you can get read through of that. So instead of saying a stop code on and truncating the protein, the rhizome will incorporate an amino acid and you’ll get full-length protein. And so there are companies developing new readthrough agents, and there are clinicians using existing read through agents like gentamycin in patients to see re-expression of the mutated protein. If you can deliver that systemically, that again is potentially exciting.

Simon Burns: Wow. Lots of exciting developments. Thank you for walking us through this, Dr. South, I really appreciate your time. We appreciate your pioneering work, both in the fields of squamous cell carcinoma and in EB, hopefully we’ll have some curative therapies, or at the very least, lots of advances coming up very shortly.

Dr. Andrew South: Yes, I hope so too. Thank you. Pleasure talking to you, Simon.

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